Journal of Alzheimer's Disease - Volume 37, issue 3

Authors: Lu, Yang | He, Hai-Jin | Zhou, Jun | Miao, Jun-Ye | Lu, Jing | He, Ying-Ge | Pan, Rong | Wei, Yan | Liu, Ying | He, Rong-Qiao

Article Type: Research Article

Abstract: Hyperphosphorylation of tau occurs in preclinical and clinical stages of Alzheimer's disease (AD), and hyperphosphorylated tau is the main constituent of the paired helical filaments in the brains of mild cognitive impairment and AD patients. While most of the work described so far focused on the relationship between hyperphosphorylation of tau and microtubule disassembly as well as axonal transport impairments, both phenomena ultimately leading to cell death, little work has been done to study the correlation between tau hyperphosphorylation and DNA damage. As we showed in this study, tau hyperphosphorylation and DNA damage co-occurred under formaldehyde treatment in N2a cells, …indicating that phosphorylated tau (p-Tau) induced by formaldehyde may be involved in DNA impairment. After phosphorylation, the effect of tau in preventing DNA from thermal denaturation was diminished, its ability to accelerate DNA renaturation was lost, and its function in protecting DNA from reactive oxygen species (ROS) attack was impaired. Thus, p-Tau is not only associated with the disassembly of the microtubule system, but also plays a crucial role in DNA impairment. Hyperphosphorylation-mediated dysfunction of tau protein in prevention of DNA structure from damage under the attack of ROS may provide novel insights into the mechanisms underlying tauopathies. Show more

Keywords: Alzheimer's disease, DNA protection, formaldehyde, GSK-3β, phosphorylation, tau hyperphosphorylation, tau protein, tauopathy

DOI: 10.3233/JAD-130602

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 551-563, 2013

Authors: Takashima, Akihiko

Article Type: Review Article

Abstract: Tauopathies are neurodegenerative diseases characterized behaviorally by dementia and neuropathologically by neurofibrillary tangles and neuronal loss. Tau gene mutations have been found in frontotemporal dementia with parkinsonism linked to chromosome 17, suggesting that mutation of tau induces tauopathy. Studies on in vitro tau aggregation show that tau forms two different intermediate aggregates—called tau oligomers and granular tau oligomers—before forming fibrils. Moreover, studies using a mouse model that expresses human tau demonstrated that the process of neurofibrillary tangle formation, rather than tangles themselves, may cause synapse loss and neuron loss. Further analyses suggest that hyperphosphorylated tau or oligomeric tau is involved …in synaptic loss, whereas granular tau oligomers are responsible for neuronal loss. Thus, different forms of tau aggregates are involved in the different pathological changes that occur in tauopathies. Show more

Keywords: Granular tau oligomer, neuron loss, synapse loss, tau fibril, tau oligomer

DOI: 10.3233/JAD-130653

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 565-568, 2013

Authors: Levarska, Lenka | Zilka, Norbert | Jadhav, Santosh | Neradil, Peter | Novak, Michal

Article Type: Research Article

Abstract: Neurofibrillary degeneration, driven by misfolded protein tau, spreads from the predisposed induction sites and advances in a topographically predictable sequence along connected brain areas. Several mouse model studies have demonstrated that some species of pathologically modified tau, namely insoluble fibrils and soluble oligomers, evoke propagation of the pathology. These results clearly show that the spreading potency of misfolded tau does not depend exclusively on its solubility and/or mutations. The candidate factor responsible for the progression of misfolded protein tau is its disease modified conformation. In this study, we address the question, whether insoluble tau complexes containing either 3R or 4R …human misfolded truncated tau (AlzTau) command distinct infectivity and spreading potency. We found that insoluble tau isolated from transgenic rats (SHR24), expressing misfolded 3R AlzTau, was able to infect cortical neurons in the area of injection in SHR72 transgenic rats expressing 4R AlzTau. However this tau was not able to spread into other brain areas. In contrast, administration of insoluble tau isolated from SHR72 transgenic rats was not only able to infect cortical neurons but also induced extensive spreading of neurofibrillary tangles in the adjacent brain areas. These findings suggest the existence of various strains of disease modified tau, tauons displaying different infectivity and spreading potency. Furthermore, the presented rat tauopathy models could serve as a tool for identification and characterization of tauons isolated from Alzheimer's disease brains that would allow stratification of Alzheimer's disease patients. Show more

Keywords: Alzheimer's disease, infectivity, neurofibrillary tangles, spreading, propagation, tau protein, tauons

DOI: 10.3233/JAD-131106

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 569-577, 2013

Authors: Yuan, Aidong | Kumar, Asok | Sasaki, Takahiro | Duff, Karen | Nixon, Ralph A.

Article Type: Research Article

Abstract: Microtubule-based axonal transport is believed to become globally disrupted in Alzheimer's disease in part due to alterations of tau expression or phosphorylation. We previously showed that axonal transport rates along retinal ganglion axons are unaffected by deletion of normal mouse tau or by overexpression of wild-type human tau. Here, we report that htau mice expressing 3-fold higher levels of human tau in the absence of mouse tau also display normal fast and slow transport kinetics despite the presence of abnormally hyperphosphorylated tau in some neurons. In addition, markers of slow transport (neurofilament light subunit) and fast transport (snap25) exhibit normal …distributions along optic axons of these mice. These studies demonstrate that human tau overexpression, even when associated with a limited degree of tau pathology, does not necessarily impair general axonal transport function in vivo. Show more

Keywords: Alzheimer's disease, fast axonal transport, neurofilament, slow axonal transport, tau, tauopathy

DOI: 10.3233/JAD-130671

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 579-586, 2013

Authors: Ding, Jun | He, Zhili | Ruan, Juan | Ma, Zilong | Liu, Ying | Gong, Chengxin | Iqbal, Khalid | Sun, Shenggang | Chen, Honghui

Article Type: Review Article

Abstract: Ciliary neurotrophic factor (CNTF) is a pleiotropic cytokine that has been fully studied for its structure, receptor, and signaling pathways and its multiplex effects on neural system, skeletal muscle, and weight control. Recent research demonstrates that CNTF also plays an important role in neurogenesis and the differentiation of neural stem cells. In this article, we summarize the general characteristics of CNTF and its function on neural stem cells, which could be a valuable therapeutic strategy in treating neurological disorders.

Keywords: Ciliary neurotrophic factor, neural stem cell, neurogenesis

DOI: 10.3233/JAD-130527

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 587-592, 2013

Authors: Ward, Sarah M. | Himmelstein, Diana S. | Lancia, Jody K. | Fu, Yifan | Patterson, Kristina R. | Binder, Lester I.

Article Type: Research Article

Abstract: The work presented herein addresses a specific portion of the tau pathology, pre-fibrillar oligomers, now thought to be important pathological components in Alzheimer's disease and other neurodegenerative tauopathies. In previous work, we generated an antibody against purified recombinant cross-linked tau dimers, called Tau Oligomeric Complex 1 (TOC1). TOC1 recognizes tau oligomers and its immunoreactivity is elevated in Alzheimer's disease brains. In this report, we expand upon the previous study to show that TOC1 selectively labels tau oligomers over monomers or polymers, and that TOC1 is also reactive in other neurodegenerative tauopathies. Using a series of deletion mutants spanning the tau …molecule, we further demonstrate that TOC1 has one continuous epitope located within amino acids 209–224, in the so-called proline rich region. Together with the previous study, our data indicates that TOC1 is a conformation-dependent antibody whose epitope is revealed upon dimerization and oligomerization, but concealed again as polymers form. This characterization of the TOC1 antibody further supports its potential as a powerful biochemical tool that can be used to better investigate the involvement of tau in neurodegenerative diseases. Show more

Keywords: Alzheimer's disease, monoclonal antibodies, oligomers, tau, tauopathy

DOI: 10.3233/JAD-131235

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 593-602, 2013

Authors: Popova, Svetlana N. | Alafuzoff, Irina

Article Type: Research Article

Abstract: Member 4 of the sodium/bile acid co-transporter family of proteins (SLC10A4) was discovered as a synaptic vesicle protein. The distribution of Slc10a4 protein in the brain has only so far been assessed in adult rats. Here, we assessed the regional distribution of SLC10A4 in aged human brain by immunohistochemistry. The protein was ubiquitously expressed, particularly in the cholinergic and monoaminergic neurons and in the lateral geniculate body. The protein expression was not influenced by the postmortem delay or fixation time. Synaptic alterations are reported to be seen in Alzheimer's disease (AD) and the suggested function of SLC10A4 as a vesicular …transporter for cholinergic neurotransmitters proposes a link between this protein and AD. With increased severity of AD-related pathology, depletion of SLC10A4 expression was noted in the transentorhinal cortex. Intriguingly, in the most severely affected cases (Braak V), two patterns were noted, i.e., those with severe depletion of SLC10A4 and those with numerous neurons displaying SLC10A4. In conclusion, assessment of the expression of SLC10A4 by means of immunohistochemistry is feasible. The observed depletion of SLC10A4 with increase in the severity of AD-related neuronal degeneration is interesting and the observation that some subjects in Braak V displayed none and some displayed numerous SLC10A4 immunoreactive neurons is intriguing. Assessment of the SLC10A4 protein in neurodegenerative diseases or diseases affecting lateral geniculate body should be carried out to investigate whether alterations in the expression of SLC10A4 in synaptic vesicles might be used as a marker of transmitter deficits (cholinergic, monoaminorgic) or other synaptic pathology. Show more

Keywords: Alzheimer's disease, hyperphosphorylated tau, immunohistochemistry, SLC10A4, synaptic vesicles

DOI: 10.3233/JAD-130548

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 603-610, 2013

Authors: Nihonmatsu-Kikuchi, Naomi | Hayashi, Yoshitaka | Yu, Xiu-jun | Tatebayashi, Yoshitaka

Article Type: Review Article

Abstract: The relationship between depression and Alzheimer's disease (AD) has always been relevant and controversial. Here, we briefly review epidemiological and biological studies that have investigated these disorders and then introduce our recent research about postmortem brains from patients with major depressive disorder (MDD). Our novel methodological approaches have revealed that MDD may be associated with an unknown type of myelin/myelination abnormalities in the frontopolar cortex. Based mainly on our findings, as well as on neuropathological observations by Braak and Braak (Acta Neuropathol 9, 197-201, 1996), we discuss the possible existence of an as yet unknown common mechanism linking the pathophysiologies …underlying both depression and AD. Show more

Keywords: Alzheimer's disease, fatty acids, flow cytometry, major depressive disorder, myelin, myelination, oligodendroglia, postmortem brain

DOI: 10.3233/JAD-130752

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 611-621, 2013

Authors: Xiong, Hui | Zheng, Chen | Wang, Jingjing | Song, Jinzhi | Zhao, Gang | Shen, Hui | Deng, Yanqiu

Article Type: Research Article

Abstract: The aim of this study was to investigate the effect of liraglutide on Alzheimer-like learning and memory impairment in mice, which were intracerebroventricularly (i.c.v.) injected with streptozotocin (STZ). Twenty-four mice were randomly divided into three groups: control (CON), AD model (STZ), and liraglutide-treated (LIR). The results show that both hyperphosphorylated tau and neurofilament proteins had deceased protein glycosylation and the tau bound to microtubules was lower in the STZ group compared to the CON group. The expression of JNK phosphorylation was higher and the number of Fluoro-Jade-B-positive degenerative neurons was increased in the STZ group as compared to both the …CON and liraglutide groups. Escape latency in the STZ group was longer than that in both the CON and LIR groups, while the number of hidden platform crossings in path length was less than that in the other two groups. Liraglutide decreased the hyperphosphorylation levels of tau and neurofilament proteins, increased protein O-glycosylation, increased tau bound to microtubules, and also significantly improved the learning and memory ability of the mice. These results suggest that the effects of liraglutide on decreasing the hyperphosphorylation of tau and neurofilament proteins by enhancing O-glycosylation of neuronal cytoskeleton protein, improving the JNK and ERK signaling pathway, and reducing neural degeneration may be related to its protective effects on AD-like learning and memory impairment induced by i.c.v. injection of STZ. Our results indicate that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease. Show more

Keywords: Alzheimer's disease, liraglutide, neurofilaments, streptozotocin, tau

DOI: 10.3233/JAD-130584

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 623-635, 2013

Authors: Yang, Yan | Zhang, Jing | Ma, Delin | Zhang, Muxun | Hu, Shuhong | Shao, Shiying | Gong, Cheng-Xin

Article Type: Research Article

Abstract: Background/Objective: Type 2 diabetes increases the risk for developing Alzheimer’s disease (AD), a progressive neurodegenerative disorder. Brain insulin resistance contributes to the pathogenesis of AD, and abnormal hyperphosphorylation of tau protein is crucial to neurodegeneration. Here we studied whether liraglutide, an agonist of glucagon-like peptide-1 (GLP-1) and a new anti-diabetic drug, can promote brain insulin signaling and inhibit tau hyperphosphorylation in the brains of type 2 diabetic rats. Methods: Type 2 diabetic rats were treated with subcutaneous administration of liraglutide (0.2 mg/kg body weight) or, as a control, saline twice a day for up to four weeks. Blood, …cerebrospinal fluid (CSF), and brain tissue (n = 7 each group) were collected for analyses after liraglutide or saline administration for one, two, three, and four weeks. Results: We found decreased CSF insulin, hyperphosphorylation of tau at AD-relevant phosphorylation sites, and decreased phosphorylation of protein kinase B (AKT) and glycogen synthase kinase-3β (GSK-3β) in the brain, which indicated decreased insulin signaling leading to overactivation of GSK-3β, a major tau kinase, in type 2 diabetic rats. Liraglutide treatment not only ameliorated hyperglycemia and peripheral insulin resistance, but also reversed these brain abnormalities in a time-dependent manner. Conclusion: Our results indicated that subcutaneous administration of liraglutide restores both peripheral and brain insulin sensitivity and ameliorates tau hyperphosphorylation in rats with type 2 diabetes. These findings support the potential use of liraglutide for the prevention and treatment of AD in individuals with type 2 diabetes. Show more

Keywords: Alzheimer's disease, AKT, GLP-1 agonist, GSK-3β, insulin, liraglutide, tau phosphorylation, type 2 diabetes

DOI: 10.3233/JAD-130491

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 637-648, 2013